Extracts of Ginkgo biloba and Hypericum perforatum (St. John's wort, SJW) herbal medicines that are widely used for the treatment of cognitive dysfunctions and for mild to moderate depression, respectively. The constituents (one or many) that are responsible for therapeutic effects are under intensive scrutiny. Over the last few years, we have collected novel evidence for neuroprotective properties of two major constituents of these two plants: bilobalide (from Ginkgo) and hyperforin (from Hypericum). Bilobalide was found to inhibit membrane breakdown during hypoxia and excitotoxicity in vitro and in vivo. In preliminary experiments, it also reduced infarct area and edema formation in a stroke model in mice. Hyperforin was found to antagonize cellular responses initiated by NMDA receptor activation such as calcium influx and cellular swelling. The present proposal is based on the hypothesis that Ginkgo and SJW extracts, and their constituents, have neuroprotective properties in acute models of brain ischemia. We will use in vitro-studies in brain slices to study edema formation and anti-edema effects of Ginkgo and SJW extracts and their pure constituents. For in vivo-studies, we will employ middle cerebral artery occlusion (MCAO) in mice to test effects of extracts and pure compounds on infarct area and edema formation. In addition, we will use microdialysis in combination with stroke to monitor metabolic parameters of ischemia (glucose, lactate, glutamate, potassium, glycerol, choline), and we will test the effects of pretreatment with botanicals on these parameters. These experiments will (a.) investigate the potential clinical utility of neuroprotective effects of two widely used herbal extracts and (b.) define the role of bilobalide and hyperforin for neuroprotective effects of Ginkgo and SJW extracts, respectively.